Sorting and Expression Profiling of Airway Cells From Humans (The SEARCH Study) (SEARCH)

• ClinicalTrials.gov Identifier: NCT02791542
• Recruitment Status: Recruiting
• First Posted: June 6, 2016
• Last Update Posted: November 3, 2022
• Sponsor: University of California, San Francisco
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); National Institute of Allergy and Infectious Diseases (NIAID)
• Information provided by (Responsible Party): University of California, San Francisco

Study Description

Brief Summary:

This will be a single site, mechanistic study of asthmatic subjects and healthy, non-asthmatic controls involving a baseline characterization visit and a research bronchoscopy visit. We will identify differences in airway epithelial epigenetic enhancer signatures in asthma, by analyzing freshly isolated airway epithelial cells from healthy controls and from well-characterized subjects with asthma.

Condition or disease
Asthma

Detailed Description:

The airway epithelium is critical for normal lung function and changes in the epithelium are central to the development of asthma. Precise regulation of gene transcription is essential for airway epithelial cell differentiation and transcription changes lead to many abnormalities seen in asthma. Despite the dominant role of enhancers in regulating transcription, little is known about how these DNA regulatory elements control airway epithelial cell transcription or about how enhancer activity differs in asthma compared to health. Closing this knowledge gap will have a major impact on our understanding of normal epithelial development and asthma. In addition, enhancer-based approaches for reprogramming the airway epithelium promise to be powerful tools for dissecting mechanism that will set the stage for developing a new class of precisely targeted treatments for asthma. Our overall goals are to identify enhancers that are important in regulation of key airway epithelial cell genes, to determine how enhancer activity changes in asthma, and to develop approaches for targeting the activity of these enhancers.

Study Design

• Study Type: Observational
• Estimated Enrollment: 70 participants
• Observational Model: Case-Control
• Time Perspective: Cross-Sectional
• Official Title: Sorting and Expression Profiling of Airway Cells From Humans (The SEARCH Study)
• Actual Study Start Date: January 2017
• Estimated Primary Completion Date: March 2023
• Estimated Study Completion Date: December 2023

Groups and Cohorts

Group/Cohort
Asthma; Participants with a history of asthma
Healthy controls; Participants without a history of asthma
Asthma Bronchoscopy sub-group; Participants with a history of asthma who will undergo the same procedures as other healthy controls with the addition of bronchoscopy
Healthy Bronchoscopy sub-group; Participants without a history of asthma who will undergo the same procedures as other healthy controls with the addition of bronchoscopy

Outcome Measures

Primary Outcome Measures :

1. Measure the genomic location of enhancers in genes previously found to be differentially expressed in asthma vs health using H3K27ac ChIP-seq and ATAC-seq on airway epithelial brushings. [ Time Frame: Between 1-12 weeks ]
   We previously identified changes in epithelial gene expression in individuals with asthma. To identify candidate enhancers that account for these changes, we will use Drop-seq, ChIPseq and ATAC-seq to analyze freshly isolated airway epithelial cells from healthy controls and from well-characterized subjects with asthma.
2. Assessment of persistence of signatures of airway inflammation [ Time Frame: 1-12 weeks and at 10-14 months ]
   Perform epithelial brush gene expression profiling and sputum induction on longitudinal samples obtained at 12 months after the initial bronchoscopy, to assess stability of type-2 and non-type-2 pathways that are dysregulated in asthma. (Achieved via the PISA sub-study)

Secondary Outcome Measures :

1. Measure gene expression by RNA sequencing in both airway brushes and BAL cells for assessment of non-type-2 pathways differentially expressed in asthma vs health. [ Time Frame: Between 1-12 weeks ]
   Perform bronchoalveolar lavage (BAL) cell flow cytometry and epithelial brush gene expression profiling to look for non-type-2 pathways that are dysregulated in asthma.

Biospecimen Retention:   Samples With DNA

Bronchial brushes and lavage Sputum, induced Whole blood Urine Serum Plasma

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes
• Sampling Method: Non-Probability Sample

Study Population

Healthy and asthmatic participants recruited from community advertising

Criteria

Inclusion Criteria (Healthy participants):

1. Male and female subjects between the ages of 18 and 70 years
2. Ability to provide written informed consent and ability to comply with the requirements of the study
3. No hyperreactivity to methacholine (PC20 FEV1 Methacholine >16 mg/mL)
4. No history of allergic rhinitis/seasonal allergies

Inclusion Criteria (Asthmatic participants):

1. Male and female subjects between the ages of 18 and 70 years
2. Ability to provide written informed consent and ability to comply with the requirements of the study
3. History of asthma
4. No use of oral or inhaled corticosteroids for the treatment of asthma during the past 6 weeks
5. Hyperreactivity to methacholine (PC20 FEV1 Methacholine < 8 mg/ml)

Exclusion Criteria:

The same exclusion criteria will apply to both Sub-studies.

1. Current smokers, defined by (a) >5 cigarettes smoked in past 12 months, and (b) ≤ 8 weeks since last time smoking; or former smokers who have a total smoking history ≥10 pack-years
2. Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study
3. Subjects with a history of lung disease other than asthma
4. Subjects with a history of a medical disease, which in the opinion of the Investigator may put the subject at extra risk from study-related procedures or because the disease may influence the results of the study
5. Prior esophageal hernia surgery.
6. Current participation in an investigational drug trial

Contacts and Locations

Contacts

Contact: Devin Roberts, BA; 628-233-1233; devin.roberts@ucsf.edu

Contact: Christine P Nguyen, BS, CCRP; 415-476-3824; christine.nguyen@ucsf.edu

Locations

United States, California

University of California, San Francisco; Recruiting

San Francisco, California, United States, 94143

Contact: Devin Roberts, BA 628-233-1233 devin.roberts@ucsf.edu

Contact: Christine P Nguyen, BS, CCRP 415-476-3824 christine.nguyen@ucsf.edu

Sponsors and Collaborators

University of California, San Francisco

National Heart, Lung, and Blood Institute (NHLBI)

National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

• Principal Investigator: Nirav Bhakta, MD, PhD; University of California, San Francisco
• Principal Investigator: Prescott Woodruff, MD, MPH; University of California, San Francisco

More Information

• Responsible Party: University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT02791542
• Other Study ID Numbers: 16-18550; R01HL138424 ( U.S. NIH Grant/Contract ); U19AI077439 ( U.S. NIH Grant/Contract )
• First Posted: June 6, 2016
• Last Update Posted: November 3, 2022
• Last Verified: November 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by University of California, San Francisco:

Asthma

Additional relevant MeSH terms:

Asthma; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases